Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=[O:7].C([O-])([O-])=O.[K+].[K+].[CH2:20](I)[CH3:21]>CN(C)C=O>[CH3:13][O:12][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:10]=1[O:11][CH2:20][CH3:21])[CH:6]=[O:7]
Reactant: CCI
Reactant: COc1cc(C=O)cc(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1c(OC)cc(C=O)cc1OC
Reaction time: 0.33 h

Procedure:
In 250 ml three necked flask, equipped with reflux condenser, mechanical stirrer, 18.2 g (100 mmol) of 3,5-dimethoxy-4-hydroxybenzaldehyde, 28 g (200 mmol) of dry K2CO3 and 100 ml of dry dimethylformamide are placed in argon condition. The mixture is stirred for 20 min in argon condition, then 42 g (21.7 ml, 270 mmol) of ethyliodide is added. The mixture is refluxed in argon condition with stirring for 20 h at 70÷100° C., and concentrated in vacuum at 50÷80° C. to dryness. Then 200 ml of water is added to the residue and the mixture is extracted with (4×100 ml) of methylene chloride. The combined organic fraction is washed with 7% NaOH solution, dried over magnesium sulfate, filtered off, concentrated in vacuum at 50÷80° C. The residue (20 g of oil) is used on the next step without further purification.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].O[C:6]1[CH:18]=[CH:17][C:9]2[S:10][C:11]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:12][C:8]=2[CH:7]=1>>[OH:3][C:1]1[C:9]2[S:10][C:11]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:12][C:8]=2[CH:7]=[CH:6][CH:2]=1.[OH:3][C:1]1[C:8]2[CH:12]=[C:11]([S:13](=[O:16])(=[O:15])[NH2:14])[S:10][C:9]=2[CH:17]=[CH:18][CH:2]=1
Reactant: NS(=O)(=O)c1cc2cc(O)ccc2s1
Reactant: CC(=O)Cl
Product: NS(=O)(=O)c1cc2c(O)cccc2s1
Product: NS(=O)(=O)c1cc2cccc(O)c2s1

Procedure:
Employing the procedure substantially as described in Example 6, but using as the acylating agent acetyl chloride as used therein or an approximately equimolar amount of the acid chlorides described in Table III and substituting for the 5-hydroxy-2-sulfamoylbenzo[b]thiophene used therein an equimolar amount of 7-hydroxy-2-sulfamoylbenzo[b]thiophene or 4-hydroxy-2-sulfamoylbenzo[b]thiophene there are produced the acyloxy-2-sulfamoylbenzo[b]thiophenes also described in Table III in accordance with the following reaction scheme.
Reaction SMILES: [O:1]=[C:2]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([OH:17])=[O:16])[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][CH3:6].[CH2:18](O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(N=C=NC2CCCCC2)CCCCC1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:8][C:4]([CH3:7])([CH2:5][CH3:6])[C:3](=[O:9])[C:2]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[O:1]
Reactant: CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C(=O)O
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 99.1 %

Procedure:
A mixture of (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidine-carboxylic acid (500 mg; 2.07 mmol), benzyl alcohol (335 mg; 3.10 mmol), dicyclohexylcarbodiimide (683 mg; 3.31 mmol), 4-dimethylaminopyridine (84 mg; 0.69 mmol) and camphorsulphonic acid (160 mg; 0.69 mmol) in methylene chloride (30 mL) was stirred overnight under a nitrogen atmosphere. The reaction mixture was filtered through Celite to remove solids and concentrated in vacuo, and the crude material was purified on a flash column (25% ethyl acetate in hexane) to obtain 680 mg of the product as a colorless oil. 1H NMR (CDCl3; 300 MHz) δ 0.85 (t, 3H); 1.19 (s, 3H); 1.22 (s, 3H); 1.61–2.25 (m, 6H); 3.46–3.56 (m, 2H); 4.58 (dm, 1H); 5.18 (d, 2H, 7.35 (br, 5H).
Reaction SMILES: [OH:1][C@H:2]([C:9]1[N:10]=[C:11]([C:14](=O)[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6].[C:17]([NH:25][NH2:26])(=[O:24])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>C(O)C.O.Cl>[OH:1][C@H:2]([C:9]1[N:10]=[C:11](/[C:14](=[N:26]/[NH:25][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)/[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6]
Reactant: NNC(=O)c1ccncc1
Reactant: CC(=O)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Agent: Cl
Solvent: O
Solvent: CCO
Product: C/C(=N\NC(=O)c1ccncc1)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Temperature: 55 °C
Reaction time: 24 h

Procedure:
1-[4-((1R,2S,3R)-1,2,3,4-Tetrahydroxy-butyl)-1H-imidazol-2-yl]-ethanone (168 mg, 0.73 mmol) was suspended in ethanol (4 ml) and water (1 ml). Isonicotinic hydrazide (110 mg, 0.80 mmol, 1.1 eq.) and hydrochloric acid (one drop, 12 N) were added, and the suspension was stirred at 55° C. for 24 hours. LCMS analysis indicated the formation of the product and the absence of starting material. The reaction mixture was cooled to room temperature, and partially concentrated in vacuo. The resulting white precipitate was collected and washed with ethanol to yield the product, as one apparent isomer, as a white solid: 136 mg (75%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[C:14]([F:16])[C:13]([NH:17][C:18]([NH:20][C:21]3[CH:34]=[CH:33][C:24]4[O:25][C:26]([F:32])([F:31])[O:27][C:28]([F:30])([F:29])[C:23]=4[CH:22]=3)=[O:19])=[C:12]([F:35])[CH:11]=2)[CH:6]=[CH:5][N:4]=1)#[N:2].C([O-])([O-])=[O:37].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+]>CC(C)=O.O>[F:35][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([F:16])[C:13]=1[NH:17][C:18]([NH:20][C:21]1[CH:34]=[CH:33][C:24]2[O:25][C:26]([F:31])([F:32])[O:27][C:28]([F:29])([F:30])[C:23]=2[CH:22]=1)=[O:19])[O:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:1]([NH2:2])=[O:37])[CH:8]=1
Reactant: N#Cc1cc(Oc2cc(F)c(NC(=O)Nc3ccc4c(c3)C(F)(F)OC(F)(F)O4)c(F)c2)ccn1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)c1cc(Oc2cc(F)c(NC(=O)Nc3ccc4c(c3)C(F)(F)OC(F)(F)O4)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-{4-[(2-cyanopyridin-4-yl)oxy]-2,6-difluorophenyl}-N′-(2,2,4,4-tetra-fluoro-4H-1,3-benzodioxin-6-yl)urea (100 mg, 0.20 mmol) in acetone (2 ml) and water (1 ml) was treated with sodium percarbonate (contain 25% H2O2, 320 mg, 2.0 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (20 ml) and water (10 ml). The organic layer was washed with water (10 ml) and brine (5 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was crystallized from methanol providing 42 mg (41%) of title compound as a white solid. 1H-NMR (DMSO-d6) δ 9.48 (s, 1H), 8.56 (d, J=6.0 Hz, 1H), 8.31 (s, 1H), 8.15 (s, 1H), 8.07 (d, J=2.2 Hz, 1H), 7.74 (s, 1H), 7.68 (dd, J=9.2, 2.7 Hz, 1H), 7.46 (d, J=2.3 Hz, 1H), 7.41 (d, J=9.3 Hz, 1H), 7.25 (m, 2H); MS GC-MS M+=515.0, RT=3.63 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9]O)[CH:6]=[CH:5][N:4]=1)#[N:2].S(Cl)([Cl:13])=O>C1(C)C=CC=CC=1>[ClH:13].[Cl:13][CH2:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:1]#[N:2])[CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cc(CO)ccn1
Solvent: Cc1ccccc1
Product: Cl
Product: N#Cc1cc(CCl)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A mixture of 2-cyano-4-hydroxymethylpyridine (0.51 g, 3.8 mmol) and thionyl chloride (0.6 ml) in toluene (20 ml) was stirred at room temperature for 1 hour. The volatiles were removed by evaporation and the residue azeotroped with toluene to give 4-chloromethyl-2-cyanopyridine hydrochloride (620 mg, 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:15][CH2:16][NH:17][CH:18]=[O:19])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14].C(N(CC)CC)C.C(=O)(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[Cl:39][C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][C:47]=1[Cl:48])[CH:43]=[O:44].Cl>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Cl:39][C:40]1[CH:41]=[C:42]([CH:43]([OH:44])[C:18]([NH:17][CH2:16][CH2:15][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:19])[CH:45]=[CH:46][C:47]=1[Cl:48]
Reactant: CCC#CCOc1ccc(CCNC=O)cc1OC
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC#CCOc1ccc(CCNC(=O)C(O)c2ccc(Cl)c(Cl)c2)cc1OC
Temperature: -78 °C
Reaction time: 4 h

Procedure:
34 g (13.0 mmol) N-[2-(3-methoxy-4-pent-2-ynyloxy-phenyl)-ethyl]-formamide and 4.3 ml (32 mmol) triethylamine are dissolved in 13 ml CH2Cl2. 1.4 g (4.7 mmol) bis(trichloromethyl) carbonate (triphosgene) in 9 ml CH2Cl2 is added at +5° C. The mixture is stirred for 4 hours at +5° C. and then cooled to −78° C. A solution of 1.43 ml (13.0 mmol) TiCl4 in 20 ml CH2Cl2 is added and the mixture is stirred for 2 hours at −40° C. 2.5 g (12.9 mmol) 3,4-dichlorobenzal-dehyde in 7 ml CH2Cl2 is added dropwise and the mixture is stirred for 17 h at room temperature. The mixture is hydrolysed with 7 ml HCl 5N, stirred 30 minutes at room temperature and washed with water. After evaporation the residue is submitted to flash-chromatography (ethyl acetate 6,hexanes 4) to give the 2-(3,4-dichloro-phenyl)-2-hydroxy-N-[2-(3-methoxy-4-pent-2-ynyloxy-phenyl)-ethyl]-acetamide.
Reaction SMILES: [O:1]=[C:2]1[N:7](C(OCC[Si](C)(C)C)=O)[CH2:6][CH2:5][N:4]2[C:17]([C:20]3[CH:25]=[N:24][CH:23]=[CH:22][N:21]=3)=[N:18][N:19]=[C:3]12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:21]1[CH:22]=[CH:23][N:24]=[CH:25][C:20]=1[C:17]1[N:4]2[CH2:5][CH2:6][NH:7][C:2](=[O:1])[C:3]2=[N:19][N:18]=1
Reactant: C[Si](C)(C)CCOC(=O)N1CCn2c(nnc2-c2cnccn2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCn2c1nnc2-c1cnccn1
Reaction time: 1 h
Yield: 191.4 %

Procedure:
To a solution of 2-(trimethylsilyl)ethyl 8-oxo-3-(pyrazin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (1.0 g, 2.9 mmol) in DCM (29 mL) was added TFA (5.7 mL, 75 mmol). After 1 h, the reaction mixture was concentrated. The crude residue was diluted with EtOAc, sonicated, and filtered to provide the desired product as a white solid (1.2 g, 95%). MS (ESI): mass calcd. for C9H8N6O, 216.1; m/z found, 217.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 9.39 (d, J=1.1 Hz, 1H), 8.77 (q, J=2.6 Hz, 2H), 8.56 (s, 1H), 4.73-4.60 (m, 2H), 3.67-3.55 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H].C>[Pd].C(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reaction time: 0.17 h

Procedure:
10% w/w palladium on charcoal (250 mg) was added to a solution of the product from step (i) (5.37 g) in ethanol (100 ml) and the mixture hydrogenated at room temperature and pressure until the theoretical amount of hydrogen had been taken up. Charcoal was added, the mixture stirred for 10 minutes then filtered through diatomaceous earth and the filtrate evaporated to dryness. The solid residue, on recrystallisation from ethyl acetate/hexane gave 4-(N-tertiary-butyloxycarbonylaminomethyl)aniline, 4.20 g: m.p. 80°-81° C.; NMR (d6DMSO) δ7.10(1H,bt) 6.88(2H,d) 6.49(2H,d), 4.92(2H,s) 3.92(2H,d), 1.38(9H,s); m/e 223(M+H)+ ; calculated for C12H18N2O2 : C, 64.8; H, 8.2; N, 12.6. found: C, 65.4; H, 8.3; N, 13.0%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][N:17]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[S-:24][C:25]#[N:26].[K+].BrBr>C(O)(=O)C>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]2[N:17]=[C:18]3[S:24][C:25]([NH2:26])=[N:22][C:19]3=[CH:20][CH:21]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)c(Oc2ccc(N)cn2)c1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1ccc(F)c(Oc2ccc3nc(N)sc3n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
To a solution of tert-butyl{3-[(5-aminopyridin-2-yl)oxy]-4-fluorophenyl}carbamate (2.50 g, 7.8 mmol) and potassium thiocyanate (2.92 g, 30 mmol) in acetic acid (30 mL) was added dropwise bromine (1.93 g, 12 mmol) under ice-cooling, and the mixture was stirred at room temperature overnight. The yellow insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution (100 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was triturated with diethyl ether to give the title compound (1.92 g, 65%) as a pale-yellow amorphous.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[S:12])([CH3:3])[CH3:2].[CH:13]([NH:16][CH2:17][C:18](O)=[O:19])([CH3:15])[CH3:14].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:13]([N:16]1[CH2:17][C:18](=[O:19])[N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])[C:11]1=[S:12])([CH3:15])[CH3:14]
Reactant: CC(C)NCC(=O)O
Reactant: CC(C)c1ccccc1N=C=S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)c1ccccc1N1C(=O)CN(C(C)C)C1=S
Yield: 43.6 %

Procedure:
The title compound was prepared by the procedure described in Example 45 using 10.0 g of 2-isopropylphenyl-isothiocyanate, 11.9 g of N-isopropyl glycine, 12.0 g of triethyl amine, and 200 mL of chloroform. Crystallization from ethanol afforded the title compound (6.8 g) as a light pink solid, m.p. 112°-114° C. Anal. Calcd. for. C15H2O N2O S: C, 65.18; H, 7.29; N, 10.13, Found: C, 65.51; H, 7.25; N, 10.32. Mass spectrum (EI, M.+) m/z 276.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](C)([CH3:19])[CH2:15]C(O)=O)=[CH:10][CH:9]=1>>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:19])([CH3:15])[CH2:1][C:2]([Cl:4])=[O:3])=[CH:10][CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(CC(=O)O)c1ccc(F)cc1
Product: CC(C)(CC(=O)Cl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.6 %

Procedure:
Oxalyl chloride (46.5 g, 0.367 mol, Aldrich) was added to a solution of 3-(4-fluorophenyl)-3-methylbutyric acid (24 g, 0.122 mol) at -10° C. while protected from moisture by a nitrogen atmosphere. The stirring mixture was allowed to warm to 25° C. and was stirred for 2 h. Fractional distillation gave 26.6 g (76%) of 3-(4-fluorophenyl)-3-methylbutyryl chloride as a clear oil, b.p., 132°-138° C.;
Reaction SMILES: Br[CH:2](C)[C:3](OC)(OC)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[C:17]([O-:20])(=[O:19])C.[K+]>CN(C)C=O.O>[CH3:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([CH:3]([CH3:2])[C:17]([OH:20])=[O:19])=[CH:9][CH:8]=1
Reactant: CC(=O)[O-]
Reactant: COc1ccc(C(OC)(OC)C(C)Br)cc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(C)C(=O)O)cc1
Temperature: 95 °C
Reaction time: 22 h

Procedure:
A mixture of 2-bromo-1,1-dimethoxy-1-(4-methoxyphenyl)-propane (0.36 g; 1.25 mmol), potassium acetate (0.15 g; 1.5 mmol) and N,N-dimethylformamide:water (6:4 v/v) (3.5 ml) is heated at 95° C. under stirring for 22 h. Usual work up gives 2-(4-methoxyphenyl)-propionic acid. 2-(1-Bromoethyl)-2-(4-methoxyphenyl)-1,3-dioxolane (0.36 g; 1.25 mmol) and 2-chloro-1,1-dimethoxy-1-(4-methoxyphenyl)-propane (0.30 g; 1.25 mmol), when reacted, separately, under the reaction conditions above described give similar results.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[S:10][C:11]([C:14]#[N:15])=[CH:12][N:13]=2)[CH:5]=[C:4]([CH2:16]O)[CH:3]=1.CN(C)C=O.P(Cl)(Cl)([Cl:25])=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[S:10][C:11]([C:14]#[N:15])=[CH:12][N:13]=2)[CH:5]=[C:4]([CH2:16][Cl:25])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cnc(Nc2cc(CO)cc(Cl)n2)s1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cnc(Nc2cc(CCl)cc(Cl)n2)s1

Procedure:
2-{[6-Chloro-4-(hydroxymethyl)pyridin-2-yl]amino}-1,3-thiazole-5-carbonitrile 11-7 (0.132 g, 0.49 mmol) was stirred in anhydrous CH2Cl2 (2 mL) under N2. N,N-Dimethylformamide (0.038 mL, 0.49 mmol) was added followed by the addition of phosphorous oxychloride (0.046 mL, 0.49 mmol). After 2.5 hours the reaction was concentrated and quenched by the addition of saturated NaHCO3 (aq). A precipitate formed which was filtered and washed with water to afford 2-{[6-chloro-4-(chloromethyl)pyridin-2-yl]amino}-1,3-thiazole-5-carbonitrile as a yellow solid. 1H NMR (DMSO-d6) δ 12.63 (bs, 1H), 8.34 (s, 1H), 7.24 (s, 1H), 7.17 (s, 1H), 4.82 (s, 2H).
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:7][CH:6]([C:8]#[N:9])[CH2:5]1)#[N:2].[NH:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1.C(#N)C.N12CCCN=C1CCCCC2>>[C:1]([CH2:3][C:4]1([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7][CH:6]([C:8]#[N:9])[CH2:5]1)#[N:2]
Reactant: N#CC=C1CC(C#N)C1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(C#N)C4)c3)ncnc21
Temperature: 25 °C

Procedure:
3-(Cyanomethylene)cyclobutanecarbonitrile (120 mg, 0.0010 mol) was combined with 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (0.1 g, 0.0003 mol) in acetonitrile (2 mL, 0.04 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (6 μL, 0.00004 mol) under nitrogen. The mixture was stirred at room temperature over the weekend. After evaporation to dryness, the crude mixture was purified by flash column, eluting with 0 to 10% MeOH in dichloromethane, to give the desired product. LCMS (M+H) 434.4.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:13][S:14](O)(=[O:16])=[O:15]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:14]([Cl:13])(=[O:16])=[O:15])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccccc21
Reactant: O=S(=O)(O)Cl
Product: CC(=O)N1CCc2cc(S(=O)(=O)Cl)ccc21
Temperature: 60 °C

Procedure:
A 1.02 g portion of 1-acetylindoline was treated with 2 mL of chlorosulfonic acid at 0° C. The mixture was heated at 60° C. for 2 h, then treated with crushed ice, filtered and dried to give 1.3 g of the title compound which was used directly for subsequent reaction. TLC: Rf=0.18, 50% EtOAc/hexane. (1H)-NMR (CDCl3) consistent with structure.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[CH:36][C:37]([C:40]([O:42]C)=[O:41])=[N:38][CH:39]=2)O1>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:34]4[CH:35]=[CH:36][C:37]([C:40]([OH:42])=[O:41])=[N:38][CH:39]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[N:15]=1
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CN1CCN(c2cc(N3CCc4ccc(-c5ccc(C(=O)O)nc5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 2, starting from 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (Example 1) and methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate (Frontier Cat. No. M2012). LCMS (M+H)+: m/z=446.3.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28]>>[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)c([N+](=O)[O-])c1
Yield: 46.9 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 510 mg of 4-fluoro-3-nitroaniline in place of the 2,4-difluoroaniline. 339 mg of N-(4-fluoro-3-nitrophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH2:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)[CH2:15][CH3:16]>>[O:13]=[C:7]([C:5]1[N:6]=[C:2]([NH:1][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH2:14][CH2:15][CH3:16])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[S:3][CH:4]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Product: CCCc1ccc(S(=O)(=O)Nc2nc(C(=O)C(=O)OCC)cs2)cc1

Procedure:
The title compound was prepared from ethyl (2-amino-4-thiazolyl)glyoxylate and 4-n-propylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (14.5 mg) with purity >90%. LCMS (pos) m/z 383.2.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][CH2:9][CH2:10][Cl:11].CN(C=O)C.[OH:17][C:18]1[N:22]([CH3:23])[N:21]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH:19]=1>O>[Cl:11][CH2:10][CH2:9][CH2:8][O:17][C:18]1[N:22]([CH3:23])[N:21]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH:19]=1
Reactant: ClCCCBr
Reactant: COC(=O)c1cc(O)n(C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCCCCl)n(C)n1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
Cesium carbonate (2.08 g, 6.4 mmol) and 1-bromo-3-chloropropane (1.6 ml) were added to a DMF solution (5 ml) of methyl 5-hydroxy-1-methyl-1H-pyrazole-3-carboxylate (0.83 g, 5.3 mmol) and the mixture was stirred at room temperature for 21 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic phase was washed with water and dried over magnesium sulfate. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:1→4:1). The purified product was concentrated to dryness under reduced pressure to obtain methyl 5-(3-chloropropoxy)-1-methyl-1H-pyrazole-3-carboxylate (1.17 g) as white solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:25][C:17]3=[C:18]4[C:22](=[CH:23][CH:24]=[C:16]3[O:15][CH2:14]2)[NH:21][CH:20]=[CH:19]4)(=O)=O)=CC=1.[NH:26]1[CH2:31][CH:30]=[C:29]([C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:34][CH:33]=2)[CH2:28][CH2:27]1>CS(C)=O.C(OCC)(=O)C>[NH:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:32]([C:29]2[CH2:30][CH2:31][N:26]([CH2:12][CH:13]3[O:25][C:17]4=[C:18]5[C:22](=[CH:23][CH:24]=[C:16]4[O:15][CH2:14]3)[NH:21][CH:20]=[CH:19]5)[CH2:27][CH:28]=2)=[CH:33]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4[nH]ccc4c3O2)cc1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C1=C(c2c[nH]c3ccccc23)CCN(CC2COc3ccc4[nH]ccc4c3O2)C1

Procedure:
A solution of 0.65 g (1.8 mmole) of (2R)-2,3-dihydro-7H-[1,4]dioxino[2,3-e]indol-2-ylmethyl 4-methylbenzenesulfonate and 0.71 g (3.6 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 30 mL of DMSO was heated at 65° C. for 4 hours. The mixture was diluted with 300 mL of ethyl acetate, washed with 200 ml portions of saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with 2-4% methanol in methylene chloride as eluant. The product fractions were combined and concentrated in vacuum, and the residue triturated with methylene chloride/hexane (1:1) to give 0.39 g of the (S)-enantiomer of the title compound as a yellow solid, m.p. 126° C., which retains one equivalent of DMSO.